Use of low-dosage erythropoietin for stimulation of endothelial progenitor cells, for organ regeneration and for slowing the progression of end-organ damage

Abstract

The present invention relates to the use of low-dosage erythropoietin for stimulation of physiological mobilization, proliferation and differentiation of endothelial progenitor cells, for stimulation of vasculogenesis, for therapy of diseases related to a dysfunction of endothelial progenitor cells, and for production of pharmaceutical compositions for treatment of such diseases as well as pharmaceutical compositions that include erythropoietin and other suitable active ingredients for stimulation of endothelial progenitor cells.

1 . The use of erythropoietin and/or derivatives for production of a pharmaceutical composition containing a dose of 1 to 90 IU/kg of body weight per week, preferably 1 to 45 IU/kg of body weight per week, for prevention or treatment of diseases, wherein the erythropoietin in this dose is suitable and designed for prevention or treatment of a human or animal patient exhibiting a) at least one dysfunction of endothelial progenitor cells, b) at least one cardiovascular risk factor such as hypertension, hypercholesterolemia, elevated asymmetric dimethylarginine (ADMA) levels, increased insulin resistance or hyperhomocysteinemia and c) at least one end-organ damage, namely left ventricular hypertrophy, microalbuminuria, cognitive dysfunction, increased thickness of the intima media in the carotid artery, proteinuria or a glomerular filtration rate of 30 to 80 ml/min.  
   
   
       2 . The use of erythropoietin and/or derivatives for production of a pharmaceutical composition containing a dose of 1 to 90 IU/kg of body weight per week, preferably 1 to 45 IU/kg of body weight per week, wherein the erythropoietin in this dose is suitable and designed for cosmetic treatment of the human or animal body, especially for treatment of wrinkles, for strengthening of the connective tissue, for protection and tightening of the skin, for protection against harmful environmental effects, for treatment of age spots, for acceleration of reepithelialization, for acceleration of hair growth and/or as makeup foundation.  
   
   
       3 . The use of erythropoietin and/or derivatives for production of a pharmaceutical composition containing a dose of 1 to 90 IU/kg of body weight per week, preferably 1 to 45 IU/kg of body weight per week, for production of a cosmetic preparation, especially for topical application, wherein the erythropoietin in this dose is suitable and designed for cosmetic treatment of the human or animal body, especially for treatment of wrinkles, for strengthening of the connective tissue, for protection and tightening of the skin, for protection against harmful environmental effects, for treatment of age spots, for acceleration of reepithelialization, for acceleration of hair growth and/or as makeup foundation.  
   
   
       4 . The use of erythropoietin and/or derivatives for production of a pharmaceutical composition containing a dose of 1 to 90 IU/kg of body weight per week, preferably 1 to 45 IU/kg of body weight per week, and/or a mixture of endothelial progenitor cells with at least one cell population usable for cell therapy, wherein the erythropoietin in this dose is suitable and designed for regeneration of tissues or vessels in a human or animal body, and wherein the mixture has been brought into contact with erythropoietin in vitro prior to application.  
   
   
       5 . The use of erythropoietin and/or derivatives for production of a pharmaceutical composition containing a dose of 1 to 90 IU/kg of body weight per week, preferably 1 to 45 IU/kg of body weight per week, and/or a mixture of endothelial progenitor cells with at least one cell population usable for cell therapy, wherein the erythropoietin in this dose is suitable and designed for regeneration of tissues or vessels in a human or animal body, and wherein the erythropoietin is administered before, after or simultaneously with application of the mixture.  
   
   
       6 . The use of erythropoietin and/or derivatives for production of a pharmaceutical composition or of a kit containing a dose of 1 to 90 IU/kg of body weight per week, preferably 1 to 45 IU/kg of body weight per week, and/or at least one chemical, thermal, mechanical or biological agent, especially a pharmacological active ingredient, for production of a pharmaceutical composition or of a kit containing erythropoietin in this dosage and the at least one chemical, thermal, mechanical or biological agent, for prevention or treatment of diseases, wherein the erythropoietin in this dose is suitable and designed for sequential, timed successive or simultaneous application of the erythropoietin with the at least one chemical, thermal, mechanical or biological agent.  
   
   
       7 - 8 . (canceled)  
   
   
       9 . The use of erythropoietin and/or derivatives for production of a pharmaceutical composition containing a dose of 1 to 90 IU/kg of body weight per week, preferably 1 to 45 IU/kg of body weight per week, wherein the erythropoietin in this dose is suitable and designed for prevention or treatment of diseases, wherein the disease is hepatic disorders such as hepatitis, cirrhosis of the liver, acute or chronic liver failure, bone and cartilage disorders or lesions, mucous membrane disorders or lesions, especially in the gastrointestinal tract, Crohn's disease, ulcerative colitis, renal function restrictions with glomerular filtration rates of 30 to 80 ml/min, microalbuminuria, proteinuria, or wounds and sequelae thereof.  
   
   
       10 . The use of erythropoietin and/or derivatives for production of a pharmaceutical composition containing a dose of 1 to 90 IU/kg of body weight per week, preferably 1 to 45 IU/kg of body weight per week, for production of a kit containing erythropoietin, endothelial progenitor cells and at least one cell population usable for cell therapy, wherein the erythropoietin is preferably present in low dosage.  
   
   
       11 - 14 . (canceled)  
   
   
       15 . The use of erythropoietin in a low dosage of 1 to 90 IU/kg of body weight per week for the therapy of pathological states or diseases of the human or animal body associated with a dysfunction of endothelial progenitor cells, and wherein the pathological states or diseases associated with a dysfunction of endothelial progenitor cells are hepatic disorders such as hepatitis, cirrhosis of the liver, acute or chronic liver failure, bone and cartilage disorders or lesions, mucous membrane disorders or lesions, especially in the gastrointestinal tract, Crohn's disease, ulcerative colitis, renal function restrictions with glomerular filtration rates of 30 to 80 ml/min, microalbuminuria, proteinuria, elevated ADMA levels or wounds and sequelae thereof.  
   
   
       16 - 18 . (canceled)  
   
   
       19 . The use of erythropoietin in a low dose, especially of 1 to 90 IU/kg of body weight per week, for the therapy of hepatic disorders such as hepatitis, cirrhosis of the liver, acute or chronic liver failure, bone and cartilage disorders or lesions, mucous membrane disorders or lesions, especially in the gastrointestinal tract, Crohn's disease, ulcerative colitis, renal function restrictions with glomerular filtration rates of 30 to 80 ml/min, microalbuminuria, proteinuria, elevated ADMA levels or wounds and/or sequelae thereof.  
   
   
       20 - 31 . (canceled)  
   
   
       32 . The use of erythropoietin for production of a transplantable endothelial preparation.  
   
   
       33 - 38 . (canceled)  
   
   
       39 . A pharmaceutical composition for stimulation of endothelial progenitor cells, for stimulation of the formation of endothelial tissue, for stimulation of vasculogenesis and/or for treatment of diseases or pathological states associated with a dysfunction of endothelial progenitor cells, comprising erythropoietin and/or a derivative, an analog, a modification or a mutein thereof as the active ingredient as well as at least one further active ingredient selected from the group comprising VEGF, PIGF, GM-CSF, an ACE inhibitor such as enalapril, ramipril or trandolapril, an AT-1 blocker such as irbesartan, lorsartan or olmesaratan, an HMG-CoA reductase inhibitor and an NO donor, preferably in a low dose, especially of 1 to 90 IU/kg of body weight per week.  
   
   
       40 . A pharmaceutical composition for prevention and/or therapy of hepatic disorders such as hepatitis, cirrhosis of the liver, acute or chronic liver failure, bone and cartilage disorders or lesions, ligament and tendon disorders or lesions, mucous membrane disorders or lesions, especially in the gastrointestinal tract, Crohn's disease, ulcerative colitis, renal function restrictions with glomerular filtration rates of 30 to 80 ml/min, microalbuminuria, proteinuria, elevated ADMA levels or wounds and sequelae thereof, comprising erythropoietin and/or a derivative, an analog, a modification or a mutein thereof as the active ingredient, preferably in a small dose, especially of 1 to 90 IU/kg of body weight per week.  
   
   
       41 - 44 . (canceled)  
   
   
       45 . A kit containing erythropoietin, endothelial progenitor cells and at least one cell population usable for cell therapy, wherein the erythropoietin is preferably present in low dosage.  
   
   
       46 . The use of erythropoietin and/or derivatives for production of a pharmaceutical composition or of a kit containing a dose of 1 to 90 IU/kg of body weight per week, preferably 1 to 45 IU/kg of body weight per week, for prevention or treatment of diseases of the human or animal body, wherein the erythropoietin in the said low dose is suitable and designed for improving, especially for promoting and/or accelerating, the integration of a mechanical or biological agent, especially an endoprosthesis, especially an implant, for example a tooth implant, a tooth replacement, a bone implant, a bone replacement, especially a joint prosthesis, a ligament/tendon replacement, such as the cruciate ligaments, or a solid organ into the implant or the body structures surrounding the endoprosthesis.  
   
   
       47 - 48 . (canceled)  
   
   
       49 . A kit containing erythropoietin in a dose of 1 to 90 IU/kg of body weight per week, preferably 1 to 45 IU/kg of body weight per week, an endoprosthesis and if necessary a cell therapeutic, preferably endothelial progenitor cells or other cell populations usable for cell therapy.  
   
   
       50 . The use of erythropoietin and/or derivatives for production of a pharmaceutical composition containing a dose of 1 to 90 IU/kg of body weight per week, wherein the erythropoietin in this dose is suitable and designed for prevention or treatment of insulin resistance.  
   
   
       51 . (canceled)  
   
   
       52 . The use of erythropoietin in a small dose of 1 to 90 IU/kg of body weight per week for therapy of insulin resistance.  
   
   
       53 . A pharmaceutical composition for prevention and/or therapy of insulin resistance, comprising erythropoietin and/or a derivative, an analog, a modification or a mutein thereof as the active ingredient, preferably in a small dose, especially of 1 to 90 IU/kg of body weight per week.